Guy A. Rouleau

Bio: Guy A. Rouleau is an academic researcher from Montreal Neurological Institute and Hospital. The author has contributed to research in topics: Genome-wide association study & Amyotrophic lateral sclerosis. The author has an hindex of 129, co-authored 884 publications receiving 65892 citations. Previous affiliations of Guy A. Rouleau include Utrecht University & University of Helsinki.

Characterization of the phenotype with cognitive impairment and protein mislocalization in SCA34

Abstract: Objective To better characterize the neurologic and cognitive profile of patients with spinocerebellar ataxia 34 (SCA34) caused by ELOVL4 mutations and to demonstrate the presence of ELOVL4 cellular localization and distribution abnormalities in skin-derived fibroblasts. Methods We investigated a 5-generation French-Canadian kindred presenting with a late-onset cerebellar ataxia and recruited age- and education-matched controls to evaluate the presence of neurocognitive impairment. Immunohistochemistry of dermal fibroblasts derived from a patient9s skin biopsy was performed. Results Patients had a late-onset slowly progressive cerebellar syndrome (mean age at onset 47 years; range 32–60 years) characterized by truncal and limb ataxia, dysarthria, hypometric saccades, and saccadic pursuits. No patient had past or current signs of erythrokeratodermia variabilis, which had previously been reported. MRI revealed cerebellar atrophy, with pontine atrophy (4 of 6 patients), and cruciform hypersignal in the pons (2 of 6 patients). Fluorodeoxyglucose-PET showed diffuse cerebellar hypometabolism in all 5 tested patients with subtle parietal hypometabolism in 3. Significant cognitive deficits were found in executive functioning, along with apparent visuospatial, attention, and psychiatric involvement. Immunohistochemistry of dermal fibroblasts showed mislocalization of the ELOVL4 protein, which appeared punctate and aggregated, supporting a dominant negative effect of the mutation on protein localization. Conclusions Our findings support the pathogenicity of ELOVL4 mutations in cerebellar dysfunction and provide a detailed characterization of the SCA34 phenotype, with neurocognitive changes typical of the cerebellar cognitive-affective syndrome.

C9orf72 hexanucleotide repeat expansions as the causative mutation for chromosome 9p21-linked amyotrophic lateral sclerosis and frontotemporal dementia.

Abstract: Objective To further assess the presence of a large hexanucleotide repeat expansion in the first intron of the C9orf72 gene identified as the genetic cause of chromosome 9p21–linked amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD) in 4 unrelated families with a conclusive linkage to c9ALS/FTD. Design A repeat-primed polymerase chain reaction assay. Setting Academic research. Participants Affected and unaffected individuals from 4 ALS/FTD families. Main Outcome Measure The amplified C9orf72 repeat expansion. Results We show that the repeat is expanded in and segregated perfectly with the disease in these 4 pedigrees. Conclusion Our findings further confirm the C9orf72 hexanucleotide repeat expansion as the causative mutation for c9ALS/FTD and strengthen the hypothesis that ALS and FTD belong to the same disease spectrum.

An 18 alanine repeat in a severe form of oculopharyngeal muscular dystrophy.

Abstract: Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant adult-onset neuromuscular disease that usually develops in the fifth or sixth decade of life and which is characterized by progressive ptosis, dysphagia and proximal limb weakness as well as a positive family history1. The disease is usually inherited with complete penetrance and without gender preference1. It is caused by trinucleotide repeat expansions that result in a lengthened polyalanine tract in the polyadenylate binding protein nuclear-1 gene (PABPN1), located on chromosome 14q11.2-q13. These polyalanine expansions referred to as (GCN)n are believed to arise from unequal allelic homologous recombination during meiosis and/or mitosis2. The wild type allele of the PABPN1 gene harbors 10 alanine codons that are located immediately downstream to the start codon in exon 1 where they code for an homopolymeric stretch of 10 alanine residues, also referred as (GCN)10. Mutant dominant PABPN1 alleles underlying OPMD range between 12 and 17 (GCN) repeats. A (GCN)11 polymorphism has been reported in North America, Europe and Japan but it does not lead to OPMD or another specific phenotype when in an heterozygous state2. However, rare cases of (GCN)11 homozygous carriers have been reported and, by comparison to individuals with (GCN)12-17 alleles, they present with relatively mild OPMD symptoms and at a later age of onset (sixties). To date, PABPN1 is the only known gene to be associated with OPMD. Interestingly, in our study based on 72 French-Canadian families, we have shown that 5% of familial cases had a (GCN)12, 40% a (GCN)13, 26% a (GCN)14, 21% a (GCN)15, 7% a (GCN)16 and finally 1% a (GCN)17 PABPN1 allele3. A relationship between the length of the (GCN) repeat and symptom severity was found because compound heterozygote carriers of (GCN)11 (GCN)13 alleles displayed a more severe phenotype than siblings who were compound heterozygous carriers of (GCN)10 (GCN)13 alleles or homozygous siblings with (GCN)11 alleles3,4. In that vein, Hill et al observed an earlier age of onset for individuals with longer repeat expansions5. However, Tondo and colleagues reported a range of symptom severity among carriers of a mutated (GCN)n of the same size, while Semmler and colleagues reported autosomal recessive OPMD cases harboring (GCN)11 alleles with severe phenotypes6,7. Therefore, it has been suggested that additional genetic and environmental factors could modulate disease expression and consequently, the correlation between severity and the polyalanine expansion size is still a subject of debate. Here, we report a family with two affected sisters who are both carriers of an unusual expansion of 18 polyalanines in PABPN1, the longest (GCN)n expansion reported to date. We believe this An 18 Alanine Repeat in a Severe Form of Oculopharyngeal Muscular Dystrophy

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

A framework for variation discovery and genotyping using next-generation DNA sequencing data

Abstract: Recent advances in sequencing technology make it possible to comprehensively catalogue genetic variation in population samples, creating a foundation for understanding human disease, ancestry and evolution. The amounts of raw data produced are prodigious and many computational steps are required to translate this output into high-quality variant calls. We present a unified analytic framework to discover and genotype variation among multiple samples simultaneously that achieves sensitive and specific results across five sequencing technologies and three distinct, canonical experimental designs. Our process includes (1) initial read mapping; (2) local realignment around indels; (3) base quality score recalibration; (4) SNP discovery and genotyping to find all potential variants; and (5) machine learning to separate true segregating variation from machine artifacts common to next-generation sequencing technologies. We discuss the application of these tools, instantiated in the Genome Analysis Toolkit (GATK), to deep whole-genome, whole-exome capture, and multi-sample low-pass (~4×) 1000 Genomes Project datasets.

Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis

Abstract: Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the cortex, brainstem and spinal cord. Its cause is unknown and it is uniformly fatal, typically within five years. About 10% of cases are inherited as an autosomal dominant trait, with high penetrance after the sixth decade. In most instances, sporadic and autosomal dominant familial ALS (FALS) are clinically similar. We have previously shown that in some but not all FALS pedigrees the disease is linked to a genetic defect on chromosome 21q (refs 8, 9). Here we report tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O2.- to O2 and H2O2 (ref. 10). Given this linkage and the potential role of free radical toxicity in other neurodenegerative disorders, we investigated SOD1 as a candidate gene in FALS. We identified 11 different SOD1 missense mutations in 13 different FALS families.

Genetic alterations during colorectal-tumor development.

Abstract: Because most colorectal carcinomas appear to arise from adenomas, studies of different stages of colorectal neoplasia may shed light on the genetic alterations involved in tumor progression. We looked for four genetic alterations (ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18) in 172 colorectal-tumor specimens representing various stages of neoplastic development. The specimens consisted of 40 predominantly early-stage adenomas from 7 patients with familial adenomatous polyposis, 40 adenomas (19 without associated foci of carcinoma and 21 with such foci) from 33 patients without familial polyposis, and 92 carcinomas resected from 89 patients. We found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas. However, ras mutations were found in only 9 percent of adenomas under 1 cm in size. Sequences on chromosome 5 that are linked to the gene for familial adenomatous polyposis were not lost in adenomas from the patients with polyposis but were lost in 29 to 35 percent of adenomas and carcinomas, respectively, from other patients. A specific region of chromosome 18 was deleted frequently in carcinomas (73 percent) and in advanced adenomas (47 percent) but only occasionally in earlier-stage adenomas (11 to 13 percent). Chromosome 17p sequences were usually lost only in carcinomas (75 percent). The four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumors. These results are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis.